Trypanosomiasis challenge estimation using the diminazene-aceturate (Berenil) index in Zebu in Gabon

A longitudinal study was conducted within a cattle ranch in Gabon to determine the diminazene aceturate (Berenil) index (DAI) in a group of Zebu, raised under low tsetse density; this measure providing an assessment of trypanosomiasis risk. The objective was to evaluate the trypanosomiasis pressure thus informing trypanosomiasis control methods and cattle management. Twenty female adult Zebu were monitored for 24 weeks during the dry season. Blood samples were collected on aweekly basis and subjected to parasitological and haematological analysis (n = 480), using the buffy-coat method and the packed cell volume value (PCV), respectively, infected animals were treated with a single intramuscular injection of diminazene aceturate (8 mg/kg). Twenty-nine single infectious events were recorded and a DAI of 1.45 was calculated. Two trypanosome species were identified: Trypanosoma congolense (96.2%) and Trypanosoma vivax (3.8%). The mean PCV value of the infected animals was lower (26.6) compared to non-infected animals (32.0). This study shows that DAI may be a useful tool to assess trypanosomiasis. However, this is a time-consumingmethod that may be improved by using randomly selected sentinel animals to adapt the chemoprophylactic schemes, hence decreasing the costs and the drug resistance risk

Alterations to Melanocortinergic, GABAergic and Cannabinoid Neurotransmission Associated with Olanzapine-Induced Weight Gain

Background/Aim: Second generation antipsychotics (SGAs) are used to treat schizophrenia but can cause serious metabolic side-effects, such as obesity and diabetes. This study examined the effects of low to high doses of olanzapine on appetite/ metabolic regulatory signals in the hypothalamus and brainstem to elucidate the mechanisms underlying olanzapineinduced obesity. Methodology/Results: Levels of pro-opiomelanocortin (POMC), neuropeptide Y (NPY) and glutamic acid decarboxylase (GAD65, enzyme for GABA synthesis) mRNA expression, and cannabinoid CB1 receptor (CB1R) binding density (using [ 3 H]SR-141716A) were examined in the arcuate nucleus (Arc) and dorsal vagal complex (DVC) of female Sprague Dawley rats following 0.25, 0.5, 1.0 or 2.0 mg/kg olanzapine or vehicle (36/day, 14-days). Consistent with its weight gain liability, olanzapine significantly decreased anorexigenic POMC and increased orexigenic NPY mRNA expression in a dose-sensitive manner in the Arc. GAD65 mRNA expression increased and CB1R binding density decreased in the Arc and DVC. Alterations to neurotransmission signals in the brain significantly correlated with body weight and adiposity. The minimum dosage threshold required to induce weight gain in the rat was 0.5 mg/kg olanzapine. Conclusions: Olanzapine-induced weight gain is associated with reduced appetite-inhibiting POMC and increased NPY. This study also supports a role for the CB1R and GABA in the mechanisms underlying weight gain side-effects, possibly b

The optimal treatment of an infectious disease with two strains

This paper explores the optimal treatment of an infectious disease in a Susceptible-Infected-Susceptible model, where there are two strains of the disease and one strain is more infectious than the other. The strains are perfectly distinguishable, instantly diagnosed and equally costly in terms of social welfare. Treatment is equally costly and effective for both strains. Eradication is not possible, and there is no superinfection. In this model, we characterise two types of fixed points: coexistence equilibria, where both strains prevail, and boundary equilibria, where one strain is asymptotically eradicated and the other prevails at a positive level. We derive regimes of feasibility that determine which equilibria are feasible for which parameter combinations. Numerically, we show that optimal policy exhibits switch points over time, and that the paths to coexistence equilibria exhibit spirals, suggesting that coexistence equilibria are never the end points of optimal paths

Activity of brigatinib (BRG) in crizotinib (CRZ) resistant patients (pts) according to ALK mutation status

Lung Cancer—Non-Small Cell MetastaticBackground: BRG is an investigational, selective ALK inhibitor with potent preclinical activity against native ALK and a broad set of mutants associated with clinical resistance to CRZ. BRG has shown promising efficacy in ALK rearranged (+) NSCLC pts previously treated with CRZ in a phase (Ph) 1/2 trial. We examined the association between BRG efficacy and ALK mutation status using tumor specimens collected after CRZ and prior to BRG treatment (tx) (baseline [BL]), and after BRG tx (Post-BL) in pts enrolled in the Ph1/2 trial and a Ph2 trial of ALK+ NSCLC pts whose disease progressed on CRZ (ALTA). Methods: Samples analysis: FoundationOne next-generation sequencing (NGS) platform. BRG activity: best response (RECIST v1.1) from BL. Data reported: Jan, 2016 for sample analyses, Nov and Dec, 2015 for Ph1/2 and ALTA clinical results, respectively. Results: Of the 301 ALK+ NSCLC pts enrolled in the Ph1/2 (N = 79) and ALTA (N = 222) trials, evaluable tumor samples were obtained from 30 pts at BL. Confirmed overall response in these pts was 63% (19/30). Secondary ALK mutations were detected in 30% (9/30) of pts. Confirmed ORR in these pts was 67% (6/9); 6 confirmed partial responses (PRs) (3 F1174L, L1196M, S1206F, and G1269A); 1 PR (G1202R) awaiting confirmation; 1 stable disease (SD) (L1196M) in a pt with 1 cycle (C = 28 days) of tx; 1 progressive disease (PD) (F1245V). Secondary ALK mutations were not detected in 70% (21/30) of pts, including 4 who were ALK fusion (-) by NGS (but ALK+ locally). Confirmed ORR in these pts was 62% (13/21); 2 CR, 11 PR, 7 SD, and 1 PD; including 3 SD and 1 PD in ALK (-) pts. Post-BL samples were collected from 5 pts (all Ph1/2), 2 of whom also had BL samples. Secondary ALK mutations, and other genetic aberrations of interest, were detected in 4 pts: 1 with F1174L (at C13 [also present at BL]; PD at C13); 2 with G1202R (at C21 [not present at BL]; PD at C13; and at C35 [BRAF G469A also detected]; PD at C35); and 1 with D1203N, G1269A, and I1171H (at C9; PD at C7). Conclusions: BRG maintains activity in CRZ resistant ALK+ NSCLC independent of the presence of secondary ALK mutations. While 2 single mutants (F1174L and G1202R) have been detected after long term tx with BRG, responses were also observed when these mutants were present at BL. Clinical trial information: NCT01449461 and NCT02094573